Alcoholism is a complex disease influenced by genetic susceptibility, environmental factors, and by interactions among genes and between genes and environment. This proposal is for a five-year renewal of the Collaborative Study on the Genetics of Alcoholism (COGA), an eight-site national collaboration with the overarching goal of identifying and characterizing genes that affect the susceptibility to develop alcohol dependence and related phenotypes. This renewal is based on the hypothesis that some of the genetically influenced differences in susceptibility are unique to alcoholism, whereas others, involving frontal lobe function (impulsivity, neural disinhibition) influence a range of related outcomes including externalizing and mood disorders and abuse of other substances. COGA has identified several genes that influence the development of alcoholism and its correlated phenotypes, including endophenotypes reflecting basic neural mechanisms. We propose to build on our successful strategies that combine the development of neurophysiological and clinical/behavioral phenotypes with extensive SNP genotyping and linkage disequilibrium analyses to identify genes underlying those phenotypes and examine mechanisms by which they influence the phenotypes. Functional studies of genes strongly associated with important phenotypes, including examination of potential coding and splicing differences and potential differences in promoter function will be conducted. A prospective study of adolescents and young adults is also proposed in which novel neurophysiological and other phenotypes will be measured and subject to genetic analyses. This will facilitate further understanding of the role of specific genes and how they interact with each other and with the environment to influence the time course of development of alcoholism and related phenotypes. These components are interrelated, and all contribute to the theme of identifying and understanding genetic and environmental factors that affect alcoholism and related phenotypes, with the expectation that this knowledge will suggest novel approaches to prevention and treatment of alcoholism and related disorders.